Cancer and Myositis
Cancer was diagnosed in 24 patients (21 DM and 3 PM), with 16 cases classified as CAM (14 DM and 2 PM). The characteristics of patients with cancer are shown in Table 2. Cancer site distribution in patients with CAM was as follows: breast (n = 4), ovarian (n = 3), lung (n = 2), colon (n = 2), cholangiocarcinoma (n = 1), cervix (n = 1), gastric (n = 1), lymphoma (n = 1), and pancreas (n = 1). Adenocarcinoma was the most common type of cancer recorded in CAM (87.5%). In the CAM group, 6 cancers were diagnosed at the same time as myositis, 6 were diagnosed during the first year before or after myositis onset, 2 between the first and second year, and 2 between the second and third year. Cancer preceded myositis in only 2 patients with CAM, by 8 months in 1 (Patient 7) and 34 months in the other (Patient 10).
The clinical and laboratory characteristics of patients with CAM were assessed comparing this group with no-CAM patients. No significant difference in sex distribution was found between the CAM group (women: 75%) and no-CAM group (women: 75.3%) (p = 1). Median age at time of myositis onset was higher in the CAM group (63 yr) than in the no-CAM group (51 yr) when both PM and DM patients were analyzed together, but the difference was not statistically significant (p = 0.18). Similarly, no statistical association was found when the analysis was performed in the DM group alone (60.4 vs. 53.2 yr, p = 1). In DM patients, the shawl sign was the only clinical characteristic seen more often in patients with CAM than in those without (p < 0.01). There were no statistical associations in either the overall group or in the separate idiopathic inflammatory myopathies (DM and PM) between the CAM and no-CAM groups when other signs and symptoms were analyzed, including peak creatine kinase, dysphagia, interstitial lung disease, and treatment response, or when dermatologic features were analyzed in DM (skin necrosis, heliotrope rash, Gottron sign, and V sign).
Anti-p155 Autoantibody Detection and Clinical Characteristics
Anti-p155 autoantibody was detected in 16 of the 85 patients with idiopathic inflammatory myopathy (19%; 95% CI, 3.4%-39.6%): 1 with PM and 15 with DM. Based on this finding, the clinical and laboratory features of patients with anti-p155 were analyzed exclusively in the DM group (Table 3). No statistical association was found between anti-p155 autoantibody and sex or age at myositis diagnosis. In contrast to anti-p155-negative DM patients, anti-p155-positive patients had the shawl sign and V sign more frequently, but differences were not significant (71% vs. 22% and 80% vs. 46%, respectively). Nonetheless, anti-p155-positive patients had a significantly lower incidence of interstitial lung disease (0% vs. 42%, p = 0.01).
Relationship Between Anti-p155 Antibody and CAM
Among the 85 patients with idiopathic inflammatory myopathy, anti-p155 autoantibody was found in 10 of the 16 patients classified as having CAM (62.5%; 95% CI, 35.4%-84.8%) but in only 6 of the 69 no-CAM patients (8.7%; 95% CI, 3.3%-18%) (p < 0.01). Neither of the 2 patients with PM and CAM had anti-p155 autoantibody. Anti-p155 was present in 10 of the 14 DM patients with CAM (71.4%) and in 5 of the 51 DM patients without CAM (9.8%) (OR, 23; 95% CI, 5.2-101.2; p < 0.001).
Among the 16 anti-p155-positive patients, cancer was diagnosed in 11 patients, with 10 cases classified as CAM (62.5%). In DM, the negative and positive predictive value of presence of the anti-p155 autoantibody for a diagnosis of CAM was 92% and 66.7%, respectively (Table 4).
Myositis-Specific and Myositis-Associated Autoantibodies
Myositis-specific autoantibodies, including any anti-synthetase autoantibodies (Jo-1, PL-7, PL-12, EJ, OJ, and KS), anti-Mi2, or anti-SRP antibodies, were present in 31 of 85 patients with idiopathic inflammatory myopathy (36.5%; 95% CI, 26.3%-47.6%), and in 22 of 65 patients with DM (33.8%; 95% CI, 22.6%-46.7%). No myositis-specific autoantibodies were detected in patients positive for anti-p155 autoantibody. In contrast, myositis-associated autoantibodies were identified in some anti-p155-positive patients (see Table 2). Among patients with CAM and negative anti-p155 autoantibody, the myositis-specific autoantibodies anti-Jo-1 and anti-Mi2 were detected separately in 2 patients (Patients 13 and 15, respectively) (see Table 2). The diagnostic accuracy of myositis-specific autoantibodies and myositis-associated autoantibodies (including anti-U-RNP, anti-Ku, anti-PM-Scl and anti-Ro) was assessed by calculating their negative and positive predictive values. In our cohort, a result negative for myositis-specific autoantibodies/myositis-associated autoantibodies had a positive predictive value of 27.8% and a negative predictive value of 89.6% for the diagnosis of CAM (31% and 86.1%, respectively, in the DM group). Use of a combined strategy in DM patients, consisting of an absence of all myositis-specific autoantibodies/myositis-associated autoantibodies analyzed or positive status to anti-p155 autoantibody, yielded a positive predictive value of 34.5% and a negative predictive value of 91% (see Table 4).
None of the anti-p155 autoantibody-positive patients presented the DQA1*0102 allele, compared with 38% of the anti-p155-negative patients (p = 0.01; OR, 15.7). We did not find the reported association24 between DQA1*0301 and presence of anti-p155 in our population, although a similar trend was observed: 16.7% of anti-p155 autoantibody-positive patients presented the DQA1*0301 allele compared with 8.3% of anti-p155-negative patients.
In this report we analyze the presence of cancer and anti-p155 autoantibody in a large cohort of patients with inflammatory idiopathic myositis and describe a number of clinical, serologic, and laboratory features of CAM and p155-positive patients.
The incidence of CAM in the current series was 19% in the complete cohort of patients with idiopathic inflammatory myopathy and 22% in the DM group. As has been reported, adenocarcinoma was the most frequent type of idiopathic inflammatory myopathy-related cancer,3,13 distributed in a broad spectrum of locations. In contrast to other studies,4,13 no association was found between age or sex and CAM, either in the overall cohort (PM/DM) or in the DM group alone. The small number of cases of CAM in PM patients precluded a separate statistical analysis in this group. Attending to the clinical and laboratory features examined, only the shawl sign showed a significant association with CAM in DM (p < 0.01).
The present study provides further evidence of the clear association between CAM and autoantibody against a 155-kDa protein in DM patients, as was previously described by Targoff et al.24 The increased risk of developing CAM in anti-p155-positive patients compared to the anti-p155-negative group was significant, with an OR of 23 (95% CI, 5.23-101.2; p < 0.001). The utility of the anti-p155 autoantibody was mainly supported by its high negative predictive value for CAM, which was 92% in DM patients. Similar results have been obtained by other authors (Table 5).
A 140-kDa protein was identified in 9 of the 16 patients with anti-p155 but, in all cases, it appeared as a weaker and apparently irrelevant protein band (data not shown). Despite their differing immunoprecipitation patterns, there is general agreement in considering anti-p155-kDa and anti-p155/140-kDa as largely identical autoantibodies because of their similar association with CAM and with certain clinical features.11,17 Both have been related to some dermatologic signs and to the absence of interstitial lung disease.15,24 Our study supports these reported associations, although the higher incidence of shawl sign and V sign in anti-p155-positive patients was not statistically significant when adjusted by the Holm procedure. We believe that the differences in protein patterns may be explained in part by the use of a different antigen source in the immunoprecipitation assays and by technical differences. Whereas Kaji, Chinoy, and Gunawardena,8,11,15 who described anti-p155/140 but not anti-p155 antibody, all used extracts from the K562 leukemia cell line as the antigen source in their immunoprecipitation experiments, both Targoff and our group used extracts from HeLa cells, a line derived from cervical cancer. The possibility that the antigen source can influence protein patterns in immunoprecipitation has been reported previously.18
In contrast to the findings of other authors,24 there was no significant association between the DQA1*0301 HLA alleles and presence of anti-p155 autoantibody in the current study, although we did detect a nonsignificant trend to a greater frequency of the DQA1*0301 allele in anti-p155-positive patients. The lack of a significant association in our population cannot be attributed to differences in population allelic frequencies, since the DQA1*0301 allele is found in about 10% of the white population of both the United States and Spain. We also documented an absence of the DQA1*0102 allele in all anti-p155-positive patients, which may indicate that this particular allele is a protective factor for development of the anti-p155 autoantibody.
To our knowledge, this is the first study in which a positive 155-kDa protein band has been described in a patient with PM, and in this case, unrelated with CAM. Anti-p155 autoantibody has been described in adult and juvenile DM, in some adult and juvenile connective tissue disease-associated myositis, and in 1 case of systemic lupus erythematosus, but not in PM patients.24 Despite evidence that anti-p155 autoantibody is not confined to DM patients alone, we believe that, in practice, anti-p155 should be considered a DM-specific autoantibody. Thus, the predictive value of this antibody in CAM should be interpreted only in adult DM patients. Its significance in juvenile DM remains uncertain.23
One limitation of the current study is related to the fact that there are no definitive criteria to establish the diagnosis of CAM. The concept of CAM is based on the idea that myositis is a paraneoplastic phenomenon. Currently, CAM is a consensus diagnosis defined according to data from historical population-based cohort studies that quantified the increased risk of cancer in idiopathic inflammatory myopathy over the time before and after myositis onset. The limit of 3 years around the diagnosis of myositis was established by consensus, but it cannot guarantee a real association between the 2 conditions. Some studies have shown an increased risk of cancer even 4 or 5 years after myositis onset.27 This issue could constitute a potential bias when analyzing the true value of anti-p155 autoantibody as a marker of paraneoplastic myositis. In addition, it should be mentioned that the incidence of CAM may have been underestimated in the current study. Four patients with PM and 15 with DM had a follow-up of less than 3 years, including 2 patients with DM and anti-p155 autoantibody who had a follow-up of 1.96 and 1.95 yr, respectively. All these patients were included in the non-CAM group, although the development of CAM could not be strictly ruled out. The median follow-up (interquartile range) of these 19 patients was 1.9 years (range, 0.6-2.3 yr). To minimize the potential bias of this factor, we repeated the statistical analysis excluding these 19 patients (data not shown), and no differences were found with regard to the previous results. Although it was not mentioned in any of the earlier reports, other authors may have had a similar problem. As described in the study, 10% of DM patients in the study by Chinoy et al8 had a follow-up shorter than 3 years, and only 58% of the 52 DM patients included in the study by Kaji et al15 had been followed for longer than 2 years.
Chinoy et al8 suggested that a serologic strategy combining positive status to anti-p155 or an absence of other myositis-specific/myositis-associated autoantibodies was a better approach to identify DM patients with CAM than anti-p155 alone. Their analysis included only myositis-specific/myositis-associated autoantibodies routinely analyzed in the local immunology laboratory: anti-Jo-1, anti-U1-RNP, anti-U3-RNP, anti-Ku, and anti-PM-Scl. We performed a similar analysis in our cohort using a larger group of myositis-specific/myositis-associated autoantibodies that included other anti-synthetase autoantibodies (PL-7, PL-12, EJ, OJ, and KS), as well as anti-Mi2, anti-SRP, and anti-Ro, in addition to those mentioned above. We found that neither this approach nor a second analysis that included only the myositis-specific/myositis-associated autoantibodies determined by Chinoy (data not shown) resulted in higher predictive values than those obtained with assessment of anti-p155 autoantibody alone. Rather than attributing this discrepancy to the differing myositis-specific/myositis-associated autoantibodies analyzed in the 2 studies, we believe it is the scant number of cases of CAM in the 2 series, which limits the power of the statistical analyses, that likely explains these differences.
Our observations provide further evidence that anti-p155 autoantibody is the best available serologic marker for CAM. Negative status to this antibody helps to rule out cancer because of its high negative predictive value, and alternatively, the presence of this autoantibody would be useful for selecting a subgroup of patients with a higher risk of CAM, in whom follow-up and complementary examinations should be more exhaustive and are likely to be more fruitful. Efforts directed toward better management of CAM should include prospective studies investigating this new serologic autoantibody.
We thank Professor Ira N. Targoff (University of Oklahoma, OK) for kindly providing the anti-p155 reference sera.
1. Airio A, Kautiainen H, Hakala M. Prognosis and mortality of polymyositis and dermatomyositis patients. Clin Rheumatol
2. Amoura Z, Duhaut P, Huong DL, et al. Tumor antigen markers for the detection of solid cancers in inflammatory myopathies. Cancer Epidemiol Biomarkers Prev
3. Andras C, Ponyi A, Constantin T, et al. Dermatomyositis and polymyositis associated with malignancy: a 21-year retrospective study. J Rheumatol
4. Basset-Seguin N, Roujeau JC, Gherardi R, Guillaume JC, Revuz J, Touraine R. Prognostic factors and predictive signs of malignancy in adult dermatomyositis. A study of 32 cases. Arch Dermatol
5. Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med
6. Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two parts). N Engl J Med
7. Buchbinder R, Forbes A, Hall S, Dennett X, Giles G. Incidence of malignant disease in biopsy-proven inflammatory myopathy. A population-based cohort study. Ann Intern Med
8. Chinoy H, Fertig N, Oddis CV, Ollier WE, Cooper RG. The diagnostic utility of myositis autoantibody testing for predicting the risk of cancer-associated myositis. Ann Rheum Dis
9. Chow WH, Gridley G, Mellemkjaer L, McLaughlin JK, Olsen JH, Fraumeni JF Jr. Cancer risk following polymyositis and dermatomyositis: a nationwide cohort study in Denmark. Cancer Causes Control
10. Fardet L, Dupuy A, Gain M, et al. Factors associated with underlying malignancy in a retrospective cohort of 121 patients with dermatomyositis. Medicine (Baltimore)
11. Gunawardena H, Betteridge ZE, McHugh NJ. Newly identified autoantibodies: relationship to idiopathic inflammatory myopathy subsets and pathogenesis. Curr Opin Rheumatol
12. Gunawardena H, Wedderburn LR, North J, et al. Clinical associations of autoantibodies to a p155/140 kDa doublet protein in juvenile dermatomyositis. Rheumatology (Oxford)
13. Hill CL, Zhang Y, Sigurgeirsson B, et al. Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study. Lancet
14. Hirakata M, Suwa A, Nagai S, et al. Anti-KS: identification of autoantibodies to asparaginyl-transfer RNA synthetase associated with interstitial lung disease. J Immunol
15. Kaji K, Fujimoto M, Hasegawa M, et al. Identification of a novel autoantibody reactive with 155 and 140 kDa nuclear proteins in patients with dermatomyositis: an association with malignancy. Rheumatology (Oxford)
16. Levine SM. Cancer and myositis: new insights into an old association. Curr Opin Rheumatol
17. Madan V, Chinoy H, Griffiths CE, Cooper RG. Defining cancer risk in dermatomyositis. Part II. Assessing diagnostic usefulness of myositis serology. Clin Exp Dermatol
18. Mimori T, Imura Y, Nakashima R, Yoshifuji H. Autoantibodies in idiopathic inflammatory myopathy: an update on clinical and pathophysiological significance. Curr Opin Rheumatol
19. Needham M, Mastaglia FL. Inclusion body myositis: current pathogenetic concepts and diagnostic and therapeutic approaches. Lancet Neurol
20. Selva-O'Callaghan A, Labrador-Horrillo M, Solans-Laque R, Simeon-Aznar CP, Martinez-Gomez X, Vilardell-Tarrés M. Myositis-specific and myositis-associated antibodies in a series of eighty-eight Mediterranean patients with idiopathic inflammatory myopathy. Arthritis Rheum
21. Sigurgeirsson B, Lindelof B, Edhag O, Allander E. Risk of cancer in patients with dermatomyositis or polymyositis. A population-based study. N Engl J Med
22. Sontheimer RD. Cutaneous features of classic dermatomyositis and amyopathic dermatomyositis. Curr Opin Rheumatol
23. Targoff IN. Autoantibodies and their significance in myositis. Curr Rheumatol Rep
24. Targoff IN, Mamyrova G, Trieu EP, et al. A novel autoantibody to a 155-kd protein is associated with dermatomyositis. Arthritis Rheum
25. Torres C, Belmonte R, Carmona L, et al. Survival, mortality and causes of death in inflammatory myopathies. Autoimmunity
26. Troyanov Y, Targoff IN, Tremblay JL, Goulet JR, Raymond Y, Senecal JL. Novel classification of idiopathic inflammatory myopathies based on overlap syndrome features and autoantibodies: analysis of 100 French Canadian patients. Medicine (Baltimore)
© 2010 Lippincott Williams & Wilkins, Inc.
27. Zantos D, Zhang Y, Felson D. The overall and temporal association of cancer with polymyositis and dermatomyositis. J Rheumatol